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Peptides for Health Benefits 2021

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Bioactives and Nutraceuticals".

Deadline for manuscript submissions: closed (30 June 2022) | Viewed by 55399

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Guest Editor
Institute of Food Science, Technology and Nutrition (ICTAN), Spanish National Research Council (CSIC), Jose Antonio Novais 10, 28040 Madrid, Spain
Interests: grains; peptides; phenolic compounds; nutritional characterization; protein quality and digestibility; bioavailability of food compounds; bioactivity; germination; fermentation; enzymatic treatments
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Guest Editor
Department of Bioactivity and Food Analysis, Institute of Food Science Research (CIAL, CSIC-UAM, CEI UAM+CSIC), Nicolás Cabrera 9, 28049 Madrid, Spain
Interests: bioactive peptides; food proteins; multifuncionality; digestion; bioavailability; inflammation-associated diseases; chemopreventive activity; peptidomics; antioxidant activity
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

In recent years, peptides have received increased interest from the pharmaceutical industry. Their high potency, specificity, and good safety profile are the main strengths of bioactive peptides, representing new and promising therapies that may fill the gap between small molecules and protein drugs. These positive attributes of peptides, along with advances in drug delivery technologies, have generated renewed interest in the discovery, optimization, and development of peptides as pharmacological therapy. Among bioactive peptides, those released from food protein sources have acquired importance as nutraceutical and active components in functional foods, because they are known to possess regulatory functions that can lead to health benefits.

This Special Issue, “Peptides for Health Benefits 2021”, will cover a selection of recent research papers, reviews, short communications, as well as perspectives in the field of bioactive peptides. It aims to cover all aspects of peptide research in relation to health promotion. In particular, this Special Issue emphasizes current knowledge and research trends concerning bioactive peptides, including the identification and quantification of peptides from new sources; methods for their production and purification; structure–function relationships; mechanisms of action; the development of novel in vitro and in vivo assays for the evaluation of their bioactivity; physiological evidence to support health benefits; and peptide stability, bioavailability, and sensory (or technofunctional) properties. Papers regarding the development of new drugs, functional foods, or nutraceuticals based on bioactive peptides will also be taken into consideration.

Dr. Cristina Martínez-Villaluenga
Dr. Blanca Hernández-Ledesma
Guest Editors

Manuscript Submission Information

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Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • human health
  • bioactive peptides
  • food peptides
  • biological activity
  • peptidomics
  • in vitro and in vivo assays
  • identification and characterization
  • functional foods
  • peptide-based therapies

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Published Papers (18 papers)

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Editorial

Jump to: Research, Review

4 pages, 189 KiB  
Editorial
Special Issue “Peptides for Health Benefits 2021”
by Cristina Martínez-Villaluenga and Blanca Hernández-Ledesma
Int. J. Mol. Sci. 2024, 25(4), 2362; https://doi.org/10.3390/ijms25042362 - 17 Feb 2024
Viewed by 602
Abstract
In recent years, non-communicable diseases (NCDs) have increased in prevalence in our society and have become a serious burden of disease worldwide [...] Full article
(This article belongs to the Special Issue Peptides for Health Benefits 2021)

Research

Jump to: Editorial, Review

11 pages, 1945 KiB  
Article
Osteostatin Inhibits M-CSF+RANKL-Induced Human Osteoclast Differentiation by Modulating NFATc1
by Lidia Ibáñez, Josep Nácher-Juan, María Carmen Terencio, María Luisa Ferrándiz and María José Alcaraz
Int. J. Mol. Sci. 2022, 23(15), 8551; https://doi.org/10.3390/ijms23158551 - 1 Aug 2022
Cited by 7 | Viewed by 1937
Abstract
Parathyroid hormone-related protein (PTHrP) C-terminal peptides regulate the metabolism of bone cells. PHTrP [107–111] (osteostatin) promotes bone repair in animal models of bone defects and prevents bone erosion in inflammatory arthritis. In addition to its positive effects on osteoblasts, osteostatin may inhibit bone [...] Read more.
Parathyroid hormone-related protein (PTHrP) C-terminal peptides regulate the metabolism of bone cells. PHTrP [107–111] (osteostatin) promotes bone repair in animal models of bone defects and prevents bone erosion in inflammatory arthritis. In addition to its positive effects on osteoblasts, osteostatin may inhibit bone resorption. The aim of this study was to determine the effects of osteostatin on human osteoclast differentiation and function. We used macrophage colony-stimulating factor (M-CSF) and receptor activator of nuclear factor κB ligand (RANKL) to induce the osteoclast differentiation of adherent human peripheral blood mononuclear cells. Tartrate-resistant acid phosphatase (TRAP) staining was performed for the detection of the osteoclasts. The function of mature osteoclasts was assessed with a pit resorption assay. Gene expression was evaluated with qRT-PCR, and nuclear factor of activated T cells, cytoplasmic 1 (NFATc1) nuclear translocation was studied by immunofluorescence. We observed that osteostatin (100, 250 and 500 nM) decreased the differentiation of osteoclasts in a concentration-dependent manner, but it did not modify the resorptive ability of mature osteoclasts. In addition, osteostatin decreased the mRNA levels of cathepsin K, osteoclast associated Ig-like receptor (OSCAR) and NFATc1. The nuclear translocation of the master transcription factor in osteoclast differentiation NFATc1 was reduced by osteostatin. Our results suggest that the anti-resorptive effects of osteostatin may be dependent on the inhibition of osteoclastogenesis. This study has shown that osteostatin controls human osteoclast differentiation in vitro through the downregulation of NFATc1. Full article
(This article belongs to the Special Issue Peptides for Health Benefits 2021)
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18 pages, 3132 KiB  
Article
De Novo Development of Mitochondria-Targeted Molecular Probes Targeting Pink1
by Shulamit Fluss Ben-Uliel, Faten Habrat Zoabi, Moriya Slavin, Hadas Sibony-Benyamini, Nir Kalisman and Nir Qvit
Int. J. Mol. Sci. 2022, 23(11), 6076; https://doi.org/10.3390/ijms23116076 - 28 May 2022
Cited by 7 | Viewed by 2439
Abstract
Mitochondria play central roles in maintaining cellular metabolic homeostasis, cell survival and cell death, and generate most of the cell’s energy. Mitochondria maintain their homeostasis by dynamic (fission and fusion) and quality control mechanisms, including mitophagy, the removal of damaged mitochondria that is [...] Read more.
Mitochondria play central roles in maintaining cellular metabolic homeostasis, cell survival and cell death, and generate most of the cell’s energy. Mitochondria maintain their homeostasis by dynamic (fission and fusion) and quality control mechanisms, including mitophagy, the removal of damaged mitochondria that is mediated mainly by the Pink1/Parkin pathway. Pink1 is a serine/threonine kinase which regulates mitochondrial function, hitherto many molecular mechanisms underlying Pink1 activity in mitochondrial homeostasis and cell fate remain unknown. Peptides are vital biological mediators that demonstrate remarkable potency, selectivity, and low toxicity, yet they have two major limitations, low oral bioavailability and poor stability. Herein, we rationally designed a linear peptide that targets Pink1 and, using straightforward chemistry, we developed molecular probes with drug-like properties to further characterize Pink1. Initially, we conjugated a cell-penetrating peptide and a cross-linker to map Pink1’s 3D structure and its interaction sites. Next, we conjugated a fluorescent dye for cell-imaging. Finally, we developed cyclic peptides with improved stability and binding affinity. Overall, we present a facile approach to converting a non-permeable linear peptide into a research tool possessing important properties for therapeutics. This is a general approach using straightforward chemistry that can be tailored for various applications by numerous laboratories. Full article
(This article belongs to the Special Issue Peptides for Health Benefits 2021)
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19 pages, 318 KiB  
Article
Characterisation of Endogenous Peptides Present in Virgin Olive Oil
by Eduardo Lopez-Huertas and Juan M. Alcaide-Hidalgo
Int. J. Mol. Sci. 2022, 23(3), 1712; https://doi.org/10.3390/ijms23031712 - 2 Feb 2022
Cited by 4 | Viewed by 1753
Abstract
The low molecular weight peptide composition of virgin olive oil (VOO) is mostly unknown. We aimed to investigate the composition of the endogenous peptides present in VOO, the protein sources from which those peptides originate and their biological activities. A water-soluble extract containing [...] Read more.
The low molecular weight peptide composition of virgin olive oil (VOO) is mostly unknown. We aimed to investigate the composition of the endogenous peptides present in VOO, the protein sources from which those peptides originate and their biological activities. A water-soluble extract containing peptides was obtained from VOO. The peptides were separated by size-exclusion using fast protein liquid chromatography, and the low molecular weight fraction (1600–700 kDa) was analysed by nanoscale liquid chromatography Orbitrap coupled with tandem mass spectrometry and de novo sequencing. Nineteen new peptides were identified by Peaks database algorithm, using the available Olea europaea (cv. Farga) genome database. Eight new peptides were also identified by Peaks de novo sequencing. The protein sources of the peptides detected in the database by Peaks DB were identified by BLAST-P search. Seed storage proteins were among the most frequent sources of VOO peptides. BIOPEP software was used to predict the biological activities of peptides and to simulate (in silico) the proteolytic activity of digestive enzymes on the detected peptide sequences. A selection of synthetic peptides was obtained for investigation of their bioactivities. Peptides VCGEAFGKA, NALLCSNS, CPANGFY, CCYSVY and DCHYFL possessed strong ACE-inhibitory and antioxidant activities in vitro. Antioxidant peptides could play a role in VOO quality. Full article
(This article belongs to the Special Issue Peptides for Health Benefits 2021)
13 pages, 1521 KiB  
Article
Erythrocytes Prevent Degradation of Carnosine by Human Serum Carnosinase
by Henry Oppermann, Stefanie Elsel, Claudia Birkemeyer, Jürgen Meixensberger and Frank Gaunitz
Int. J. Mol. Sci. 2021, 22(23), 12802; https://doi.org/10.3390/ijms222312802 - 26 Nov 2021
Cited by 13 | Viewed by 1821
Abstract
The naturally occurring dipeptide carnosine (β-alanyl-l-histidine) has beneficial effects in different diseases. It is also frequently used as a food supplement to improve exercise performance and because of its anti-aging effects. Nevertheless, after oral ingestion, the dipeptide is not detectable in [...] Read more.
The naturally occurring dipeptide carnosine (β-alanyl-l-histidine) has beneficial effects in different diseases. It is also frequently used as a food supplement to improve exercise performance and because of its anti-aging effects. Nevertheless, after oral ingestion, the dipeptide is not detectable in human serum because of rapid degradation by serum carnosinase. At the same time, intact carnosine is excreted in urine up to five hours after intake. Therefore, an unknown compartment protecting the dipeptide from degradation has long been hypothesized. Considering that erythrocytes may constitute this compartment, we investigated the uptake and intracellular amounts of carnosine in human erythrocytes cultivated in the presence of the dipeptide and human serum using liquid chromatography–mass spectrometry. In addition, we studied carnosine’s effect on ATP production in red blood cells and on their response to oxidative stress. Our experiments revealed uptake of carnosine into erythrocytes and protection from carnosinase degradation. In addition, no negative effect on ATP production or defense against oxidative stress was observed. In conclusion, our results for the first time demonstrate that erythrocytes can take up carnosine, and, most importantly, thereby prevent its degradation by human serum carnosinase. Full article
(This article belongs to the Special Issue Peptides for Health Benefits 2021)
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19 pages, 18851 KiB  
Article
IAF, QGF, and QDF Peptides Exhibit Cholesterol-Lowering Activity through a Statin-like HMG-CoA Reductase Regulation Mechanism: In Silico and In Vitro Approach
by Mariana Silva, Biane Philadelpho, Johnnie Santos, Victória Souza, Caio Souza, Victória Santiago, Jaff Silva, Carolina Souza, Francine Azeredo, Marcelo Castilho, Eduardo Cilli and Ederlan Ferreira
Int. J. Mol. Sci. 2021, 22(20), 11067; https://doi.org/10.3390/ijms222011067 - 14 Oct 2021
Cited by 11 | Viewed by 3289
Abstract
In this study, in silico approaches are employed to investigate the binding mechanism of peptides derived from cowpea β-vignin and HMG-CoA reductase. With the obtained information, we designed synthetic peptides to evaluate their in vitro enzyme inhibitory activity. In vitro, the total protein [...] Read more.
In this study, in silico approaches are employed to investigate the binding mechanism of peptides derived from cowpea β-vignin and HMG-CoA reductase. With the obtained information, we designed synthetic peptides to evaluate their in vitro enzyme inhibitory activity. In vitro, the total protein extract and <3 kDa fraction, at 5000 µg, support this hypothesis (95% and 90% inhibition of HMG-CoA reductase, respectively). Ile-Ala-Phe, Gln-Gly-Phe, and Gln-Asp-Phe peptides were predicted to bind to the substrate binding site of HMGCR via HMG-CoAR. In silico, it was established that the mechanism of HMG-CoA reductase inhibition largely entailed mimicking the interactions of the decalin ring of simvastatin and via H-bonding; in vitro studies corroborated the predictions, whereby the HMG-CoA reductase activity was decreased by 69%, 77%, and 78%, respectively. Our results suggest that Ile-Ala-Phe, Gln-Gly-Phe, and Gln-Asp-Phe peptides derived from cowpea β-vignin have the potential to lower cholesterol synthesis through a statin-like regulation mechanism. Full article
(This article belongs to the Special Issue Peptides for Health Benefits 2021)
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17 pages, 4082 KiB  
Article
Intranasal Delivery of RGD-Containing Osteopontin Heptamer Peptide Confers Neuroprotection in the Ischemic Brain and Augments Microglia M2 Polarization
by Dashdulam Davaanyam, Il-Doo Kim and Ja-Kyeong Lee
Int. J. Mol. Sci. 2021, 22(18), 9999; https://doi.org/10.3390/ijms22189999 - 16 Sep 2021
Cited by 15 | Viewed by 3015
Abstract
Osteopontin (OPN), a phosphorylated glycoprotein, is induced in response to tissue damage and inflammation in various organs, including the brain. In our previous studies, we reported the robust neuroprotective effects of the icosamer OPN peptide OPNpt20, containing arginine-glycine-aspartic acid (RGD) and serine-leucine-alanine-tyrosine (SLAY) [...] Read more.
Osteopontin (OPN), a phosphorylated glycoprotein, is induced in response to tissue damage and inflammation in various organs, including the brain. In our previous studies, we reported the robust neuroprotective effects of the icosamer OPN peptide OPNpt20, containing arginine-glycine-aspartic acid (RGD) and serine-leucine-alanine-tyrosine (SLAY) motifs, in an animal model of transient focal ischemia and demonstrated that its anti-inflammatory, pro-angiogenic, and phagocytosis inducing functions are responsible for the neuroprotective effects. In the present study, we truncated OPNpt20 to 13 or 7 amino acid peptides containing RGD (R) and/or SLAY (S) motifs (OPNpt13RS, OPNpt7R, OPNpt7RS, and OPNpt7S), and their neuroprotective efficacy was examined in a rat middle cerebral artery occlusion (MCAO) model. Intranasal administration of all four peptides significantly reduced infarct volume; OPNpt7R (VPNGRGD), the 7-amino-acid peptide containing an RGD motif, was determined to be the most potent, with efficacy comparable to that of OPNpt20. Additionally, sensory–motor functional deficits of OPNpt7R-administered MCAO animals were significantly improved, as indicated by the modified neurological severity scores and rotarod test. Notably, the expression of M1 markers was suppressed, whereas that of M2 markers (Arginase 1, CD206, and VEGF) was significantly enhanced in OPNpt7R-treated primary microglia cultures. Inflammation resolution by OPNpt7R was further confirmed in MCAO animals, in which upregulation of anti-inflammatory cytokines (Arg1, IL-10, IL-4, and CD36) and enhanced efferocytosis were detected. Moreover, studies using three mutant peptides (OPNpt7R-RAA or OPNpt7R-RAD, where RGD was replaced with RAA or RAD, respectively, and OPNpt7R-sc containing scrambled sequences) revealed that the RGD motif plays a vital role in conferring neuroprotection. In conclusion, the RGD-containing OPN heptamer OPNpt7R exhibits neuroprotective effects in the post-ischemic brain by suppressing M1 markers and augmenting M2 polarization of microglia and the RGD motif plays a critical role in these activities. Full article
(This article belongs to the Special Issue Peptides for Health Benefits 2021)
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19 pages, 4342 KiB  
Article
Analogs of a Natural Peptaibol Exert Anticancer Activity in Both Cisplatin- and Doxorubicin-Resistant Cells and in Multicellular Tumor Spheroids
by Naike Casagrande, Cinzia Borghese, Laura Gabbatore, Laura Morbiato, Marta De Zotti and Donatella Aldinucci
Int. J. Mol. Sci. 2021, 22(16), 8362; https://doi.org/10.3390/ijms22168362 - 4 Aug 2021
Cited by 14 | Viewed by 2176
Abstract
Peptaibols, by disturbing the permeability of phospholipid membranes, can overcome anticancer drug resistance, but their natural hydrophobicity hampers their administration. By a green peptide synthesis protocol, we produced two water-soluble analogs of the peptaibol trichogin GA IV, termed K6-Lol and K6-NH2. To reduce [...] Read more.
Peptaibols, by disturbing the permeability of phospholipid membranes, can overcome anticancer drug resistance, but their natural hydrophobicity hampers their administration. By a green peptide synthesis protocol, we produced two water-soluble analogs of the peptaibol trichogin GA IV, termed K6-Lol and K6-NH2. To reduce production costs, we successfully explored the possibility of changing the naturally occurring 1,2-aminoalcohol leucinol to a C-terminal amide. Peptaibol activity was evaluated in ovarian cancer (OvCa) and Hodgkin lymphoma (HL) cell lines. Peptaibols exerted comparable cytotoxic effects in cancer cell lines that were sensitive—and had acquired resistance—to cisplatin and doxorubicin, as well as in the extrinsic-drug-resistant OvCa 3-dimensional spheroids. Peptaibols, rapidly taken up by tumor cells, deeply penetrated and killed OvCa-spheroids. They led to cell membrane permeabilization and phosphatidylserine exposure and were taken up faster by cancer cells than normal cells. They were resistant to proteolysis and maintained a stable helical structure in the presence of cancer cells. In conclusion, these promising results strongly point out the need for further preclinical evaluation of our peptaibols as new anticancer agents. Full article
(This article belongs to the Special Issue Peptides for Health Benefits 2021)
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10 pages, 1246 KiB  
Article
Histatin-1 Attenuates LPS-Induced Inflammatory Signaling in RAW264.7 Macrophages
by Sang Min Lee, Kyung-No Son, Dhara Shah, Marwan Ali, Arun Balasubramaniam, Deepak Shukla and Vinay Kumar Aakalu
Int. J. Mol. Sci. 2021, 22(15), 7856; https://doi.org/10.3390/ijms22157856 - 23 Jul 2021
Cited by 29 | Viewed by 3745
Abstract
Macrophages play a critical role in the inflammatory response to environmental triggers, such as lipopolysaccharide (LPS). Inflammatory signaling through macrophages and the innate immune system are increasingly recognized as important contributors to multiple acute and chronic disease processes. Nitric oxide (NO) is a [...] Read more.
Macrophages play a critical role in the inflammatory response to environmental triggers, such as lipopolysaccharide (LPS). Inflammatory signaling through macrophages and the innate immune system are increasingly recognized as important contributors to multiple acute and chronic disease processes. Nitric oxide (NO) is a free radical that plays an important role in immune and inflammatory responses as an important intercellular messenger. In addition, NO has an important role in inflammatory responses in mucosal environments such as the ocular surface. Histatin peptides are well-established antimicrobial and wound healing agents. These peptides are important in multiple biological systems, playing roles in responses to the environment and immunomodulation. Given the importance of macrophages in responses to environmental triggers and pathogens, we investigated the effect of histatin-1 (Hst1) on LPS-induced inflammatory responses and the underlying molecular mechanisms in RAW264.7 (RAW) macrophages. LPS-induced inflammatory signaling, NO production and cytokine production in macrophages were tested in response to treatment with Hst1. Hst1 application significantly reduced LPS-induced NO production, inflammatory cytokine production, and inflammatory signaling through the JNK and NF-kB pathways in RAW cells. These results demonstrate that Hst1 can inhibit LPS-induced inflammatory mediator production and MAPK signaling pathways in macrophages. Full article
(This article belongs to the Special Issue Peptides for Health Benefits 2021)
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16 pages, 3384 KiB  
Article
Direct and Indirect Biomimetic Peptide Modification of Alginate: Efficiency, Side Reactions, and Cell Response
by Anna Golunova, Nadiia Velychkivska, Zuzana Mikšovská, Václav Chochola, Josef Jaroš, Aleš Hampl, Ognen Pop-Georgievski and Vladimír Proks
Int. J. Mol. Sci. 2021, 22(11), 5731; https://doi.org/10.3390/ijms22115731 - 27 May 2021
Cited by 12 | Viewed by 4759
Abstract
In the fast-developing field of tissue engineering there is a constant demand for new materials as scaffolds for cell seeding, which can better mimic a natural extracellular matrix as well as control cell behavior. Among other materials, polysaccharides are widely used for this [...] Read more.
In the fast-developing field of tissue engineering there is a constant demand for new materials as scaffolds for cell seeding, which can better mimic a natural extracellular matrix as well as control cell behavior. Among other materials, polysaccharides are widely used for this purpose. One of the main candidates for scaffold fabrication is alginate. However, it lacks sites for cell adhesion. That is why one of the steps toward the development of suitable scaffolds for cells is the introduction of the biofunctionality to the alginate structure. In this work we focused on bone-sialoprotein derived peptide (TYRAY) conjugation to the molecule of alginate. Here the comparison study on four different approaches of peptide conjugation was performed including traditional and novel modification methods, based on 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide/N-hydroxy succinimide (EDC/NHS), 4-(4,6-dimethoxy-1,3,5-triazine-2-yl)-4-methylmorpholinium chloride (DMTMM), thiol-Michael addition and Cu-catalyzed azide–alkyne cycloaddition reactions. It was shown that the combination of the alginate amidation with the use of and subsequent Cu-catalyzed azide–alkyne cycloaddition led to efficient peptide conjugation, which was proven with both NMR and XPS methods. Moreover, the cell culture experiment proved the positive effect of peptide presence on the adhesion of human embryonic stem cells. Full article
(This article belongs to the Special Issue Peptides for Health Benefits 2021)
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12 pages, 1669 KiB  
Article
Diabetes Affects the Pituitary Adenylate Cyclase-Activating Polypeptide (PACAP)-Like Immunoreactive Enteric Neurons in the Porcine Digestive Tract
by Katarzyna Palus, Michał Bulc, Jarosław Całka, Łukasz Zielonka and Marcin Nowicki
Int. J. Mol. Sci. 2021, 22(11), 5727; https://doi.org/10.3390/ijms22115727 - 27 May 2021
Cited by 7 | Viewed by 2471
Abstract
Diabetic gastroenteropathy is a common complication, which develops in patients with long-term diabetes. The pituitary adenylate cyclase-activating polypeptide (PACAP) is a neuropeptide known for its cytoprotective properties and plays an important role in neuronal development, neuromodulation and neuroprotection. The present study was designed [...] Read more.
Diabetic gastroenteropathy is a common complication, which develops in patients with long-term diabetes. The pituitary adenylate cyclase-activating polypeptide (PACAP) is a neuropeptide known for its cytoprotective properties and plays an important role in neuronal development, neuromodulation and neuroprotection. The present study was designed to elucidate, for the first time, the impact of prolonged hyperglycaemia conditions on a population of PACAP-like immunoreactive neurons in selected parts of the porcine gastrointestinal tract. The experiment was conducted on 10 juvenile female pigs assigned to two experimental groups: The DM group (pigs with streptozocin-induced diabetes) and the C group (control pigs). Diabetes conditions were induced by a single intravenous injection of streptozocin. Six weeks after the induction of diabetes, all animals were euthanised and further collected, and fixed fragments of the stomach, duodenum, jejunum, ileum and descending colon were processed using the routine double-labelling immunofluorescence technique. Streptozotocin-induced hyperglycaemia caused a significant increase in the population of PACAP-containing enteric neurons in the porcine stomach, small intestines and descending colon. The recorded changes may result from the direct toxic effect of hyperglycaemia on the ENS neurons, oxidative stress or inflammatory conditions accompanying hyperglycaemia and suggest that PACAP is involved in regulatory processes of the GIT function in the course of diabetes. Full article
(This article belongs to the Special Issue Peptides for Health Benefits 2021)
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Review

Jump to: Editorial, Research

20 pages, 1615 KiB  
Review
Lunasin as a Promising Plant-Derived Peptide for Cancer Therapy
by Stephanny Miranda Alves de Souza, Blanca Hernández-Ledesma and Theo Luiz Ferraz de Souza
Int. J. Mol. Sci. 2022, 23(17), 9548; https://doi.org/10.3390/ijms23179548 - 23 Aug 2022
Cited by 7 | Viewed by 3094
Abstract
Cancer has become one of the main public health problems worldwide, demanding the development of new therapeutic agents that can help reduce mortality. Lunasin is a soybean peptide that has emerged as an attractive option because its preventive and therapeutic actions against cancer. [...] Read more.
Cancer has become one of the main public health problems worldwide, demanding the development of new therapeutic agents that can help reduce mortality. Lunasin is a soybean peptide that has emerged as an attractive option because its preventive and therapeutic actions against cancer. In this review, we evaluated available research on lunasin’s structure and mechanism of action, which should be useful for the development of lunasin-based therapeutic products. We described data on its primary, secondary, tertiary, and possible quaternary structure, susceptibility to post-translational modifications, and structural stability. These characteristics are important for understanding drug activity and characterizing lunasin products. We also provided an overview of research on lunasin pharmacokinetics and safety. Studies examining lunasin’s mechanisms of action against cancer were reviewed, highlighting reported activities, and known molecular partners. Finally, we briefly discussed commercially available lunasin products and potential combination therapeutics. Full article
(This article belongs to the Special Issue Peptides for Health Benefits 2021)
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13 pages, 330 KiB  
Review
Non-Opioid Peptides Targeting Opioid Effects
by Katarzyna Kaczyńska and Piotr Wojciechowski
Int. J. Mol. Sci. 2021, 22(24), 13619; https://doi.org/10.3390/ijms222413619 - 19 Dec 2021
Cited by 5 | Viewed by 3262
Abstract
Opioids are the most potent widely used analgesics, primarily, but not exclusively, in palliative care. However, they are associated with numerous side effects, such as tolerance, addiction, respiratory depression, and cardiovascular events. This, in turn, can result in their overuse in cases of [...] Read more.
Opioids are the most potent widely used analgesics, primarily, but not exclusively, in palliative care. However, they are associated with numerous side effects, such as tolerance, addiction, respiratory depression, and cardiovascular events. This, in turn, can result in their overuse in cases of addiction, the need for dose escalation in cases of developing tolerance, and the emergence of dose-related opioid toxicity, resulting in respiratory depression or cardiovascular problems that can even lead to unintentional death. Therefore, a very important challenge for researchers is to look for ways to counteract the side effects of opioids. The use of peptides and their related compounds, which have been shown to modulate the effects of opioids, may provide such an opportunity. This short review is a compendium of knowledge about the most important and recent findings regarding selected peptides and their modulatory effects on various opioid actions, including cardiovascular and respiratory responses. In addition to the peptides more commonly reported in the literature in the context of their pro- and/or anti-opioid activity—such as neuropeptide FF (NPFF), cholecystokinin (CCK), and melanocyte inhibiting factor (MIF)—we also included in the review nociceptin/orphanin (N/OFQ), ghrelin, oxytocin, endothelin, and venom peptides. Full article
(This article belongs to the Special Issue Peptides for Health Benefits 2021)
26 pages, 1240 KiB  
Review
Role of Nociceptin/Orphanin FQ-NOP Receptor System in the Regulation of Stress-Related Disorders
by Massimo Ubaldi, Nazzareno Cannella, Anna Maria Borruto, Michele Petrella, Maria Vittoria Micioni Di Bonaventura, Laura Soverchia, Serena Stopponi, Friedbert Weiss, Carlo Cifani and Roberto Ciccocioppo
Int. J. Mol. Sci. 2021, 22(23), 12956; https://doi.org/10.3390/ijms222312956 - 30 Nov 2021
Cited by 15 | Viewed by 4388
Abstract
Nociceptin/orphanin FQ (N/OFQ) is a 17-residue neuropeptide that binds the nociceptin opioid-like receptor (NOP). N/OFQ exhibits nucleotidic and aminoacidics sequence homology with the precursors of other opioid neuropeptides but it does not activate either MOP, KOP or DOP receptors. Furthermore, opioid neuropeptides do [...] Read more.
Nociceptin/orphanin FQ (N/OFQ) is a 17-residue neuropeptide that binds the nociceptin opioid-like receptor (NOP). N/OFQ exhibits nucleotidic and aminoacidics sequence homology with the precursors of other opioid neuropeptides but it does not activate either MOP, KOP or DOP receptors. Furthermore, opioid neuropeptides do not activate the NOP receptor. Generally, activation of N/OFQ system exerts anti-opioids effects, for instance toward opioid-induced reward and analgesia. The NOP receptor is widely expressed throughout the brain, whereas N/OFQ localization is confined to brain nuclei that are involved in stress response such as amygdala, BNST and hypothalamus. Decades of studies have delineated the biological role of this system demonstrating its involvement in significant physiological processes such as pain, learning and memory, anxiety, depression, feeding, drug and alcohol dependence. This review discusses the role of this peptidergic system in the modulation of stress and stress-associated psychiatric disorders in particular drug addiction, mood, anxiety and food-related associated-disorders. Emerging preclinical evidence suggests that both NOP agonists and antagonists may represent a effective therapeutic approaches for substances use disorder. Moreover, the current literature suggests that NOP antagonists can be useful to treat depression and feeding-related diseases, such as obesity and binge eating behavior, whereas the activation of NOP receptor by agonists could be a promising tool for anxiety. Full article
(This article belongs to the Special Issue Peptides for Health Benefits 2021)
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23 pages, 7352 KiB  
Review
Ezrin Peptide Therapy from HIV to COVID: Inhibition of Inflammation and Amplification of Adaptive Anti-Viral Immunity
by Rupert D. Holms and Ravshan I. Ataullakhanov
Int. J. Mol. Sci. 2021, 22(21), 11688; https://doi.org/10.3390/ijms222111688 - 28 Oct 2021
Cited by 8 | Viewed by 3678
Abstract
Human Ezrin Peptides (HEPs) are inhibitors of expression of IL-6 and other inflammatory cytokines, amplifiers of adaptive B cell and T cell immunity and enhancers of tissue repair. The mutation stable C-terminus of HIV gp120, mimics 69% of the “Hep-receptor”, a zipped [...] Read more.
Human Ezrin Peptides (HEPs) are inhibitors of expression of IL-6 and other inflammatory cytokines, amplifiers of adaptive B cell and T cell immunity and enhancers of tissue repair. The mutation stable C-terminus of HIV gp120, mimics 69% of the “Hep-receptor”, a zipped α-helical structure in the middle of the α domain of human ezrin protein. Synthetic peptides homologous to the Hep-receptor of ezrin of five to fourteen amino acids, activate anti-viral immunity against a wide range of viruses (HIV, HCV, herpes, HPV, influenza and other human respiratory viruses). Human Ezrin Peptide One (HEP1) TEKKRRETVEREKE (brand name Gepon, registered for human use in Russia from 2001) is a successful treatment for opportunistic infections in HIV-infected patients. That treats HEP1and prevents mucosal candidiasis, herpes zoster outbreaks and infection-induced chronic diarrhea. There are clinical publications in Russian on the successful treatments of chronic recurrent vaginal candidiasis, acute and chronic enterocolitis and dysbacteriosis, which are accompanied by normalization of the mucosal microbiome, and the decline or disappearance of inflammation. HEP1 is also an effective treatment and prevention for recurrent inflammation and ulceration in the stomach, duodenum and colon. HEP1 and RepG3 GEKKRRETVEREGG (a derivative of HEP1) have been used successfully as an inhaled spray peptide solution to treat a small number of human volunteers with mild-to-moderate COVID, resulting from SARS-CoV-2 infection, based on earlier successes in treating acute viral respiratory disease with inflammatory complications. Ezrin peptides seem to correct a dysregulation of innate immune responses to SARS-CoV-2. They are also adjuvants of B cell adaptive immunity and increase antibody titres, resulting in protection from lethal virus infection of mice. In a clinical study in Moscow, orally administered HEP1 was shown to enhance antibody-titres produced in response to hepatitis-B vaccination. These very preliminary but promising results with ezrin peptide treatment of COVID must be replicated in large-scale randomised placebo controlled clinical studies, to be verified. Full article
(This article belongs to the Special Issue Peptides for Health Benefits 2021)
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21 pages, 939 KiB  
Review
Biphalin—A Potent Opioid Agonist—As a Panacea for Opioid System-Dependent Pathophysiological Diseases?
by Patrycja Redkiewicz, Jolanta Dyniewicz and Aleksandra Misicka
Int. J. Mol. Sci. 2021, 22(21), 11347; https://doi.org/10.3390/ijms222111347 - 21 Oct 2021
Cited by 5 | Viewed by 2297
Abstract
Biphalin, one of the opioid agonists, is a dimeric analog of enkephalin with a high affinity for opioid receptors. Opioid receptors are widespread in the central nervous system and in peripheral neuronal and non-neuronal tissues. Hence, these receptors and their agonists, which play [...] Read more.
Biphalin, one of the opioid agonists, is a dimeric analog of enkephalin with a high affinity for opioid receptors. Opioid receptors are widespread in the central nervous system and in peripheral neuronal and non-neuronal tissues. Hence, these receptors and their agonists, which play an important role in pain blocking, may also be involved in the regulation of other physiological functions. Biphalin was designed and synthesized in 1982 by Lipkowski as an analgesic peptide. Extensive further research in various laboratories on the antinociceptive effects of biphalin has shown its excellent properties. It has been demonstrated that biphalin exhibits an analgesic effect in acute, neuropathic, and chronic animal pain models, and is 1000 times more potent than morphine when administered intrathecally. In the course of the broad conducted research devoted primarily to the antinociceptive effect of this compound, it has been found that biphalin may also potentially participate in the regulation of other opioid system-dependent functions. Nearly 40 years of research on the properties of biphalin have shown that it may play a beneficial role as an antiviral, antiproliferative, anti-inflammatory, and neuroprotective agent, and may also affect many physiological functions. This integral review analyzes the literature on the multidirectional biological effects of biphalin and its potential in the treatment of many opioid system-dependent pathophysiological diseases. Full article
(This article belongs to the Special Issue Peptides for Health Benefits 2021)
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16 pages, 1047 KiB  
Review
Pituitary Adenylate Cyclase-Activating Polypeptide (PACAP) in Physiological and Pathological Processes within the Gastrointestinal Tract: A Review
by Aleksandra Karpiesiuk and Katarzyna Palus
Int. J. Mol. Sci. 2021, 22(16), 8682; https://doi.org/10.3390/ijms22168682 - 12 Aug 2021
Cited by 21 | Viewed by 2930
Abstract
Pituitary adenylate cyclase-activating polypeptide (PACAP) is a neuropeptide widely distributed in the central nervous system (CNS) and many peripheral organs, such as the digestive tract, endocrine, reproductive and respiratory systems, where it plays different regulatory functions and exerts a cytoprotective effect. The multifarious [...] Read more.
Pituitary adenylate cyclase-activating polypeptide (PACAP) is a neuropeptide widely distributed in the central nervous system (CNS) and many peripheral organs, such as the digestive tract, endocrine, reproductive and respiratory systems, where it plays different regulatory functions and exerts a cytoprotective effect. The multifarious physiological effects of PACAP are mediated through binding to different G protein-coupled receptors, including PAC1 (PAC1-R), VPAC1 (VPAC1-R) and VPAC2 (VPAC2-R) receptors. In the gastrointestinal (GI) tract, PACAP plays an important regulatory function. PACAP stimulates the secretion of digestive juices and hormone release, regulates smooth muscle contraction, local blood flow, cell migration and proliferation. Additionally, there are many reports confirming the involvement of PACAP in pathological processes within the GI tract, including inflammatory states, neuronal injury, diabetes, intoxication and neoplastic processes. The purpose of this review is to summarize the distribution and pleiotropic action of PACAP in the control of GI tract function and its cytoprotective effect in the course of GI tract disorders. Full article
(This article belongs to the Special Issue Peptides for Health Benefits 2021)
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44 pages, 28891 KiB  
Review
Peptides Derived from Growth Factors to Treat Alzheimer’s Disease
by Suzanne Gascon, Jessica Jann, Chloé Langlois-Blais, Mélanie Plourde, Christine Lavoie and Nathalie Faucheux
Int. J. Mol. Sci. 2021, 22(11), 6071; https://doi.org/10.3390/ijms22116071 - 4 Jun 2021
Cited by 14 | Viewed by 4618
Abstract
Alzheimer’s disease (AD) is a devastating neurodegenerative disease characterized by progressive neuron losses in memory-related brain structures. The classical features of AD are a dysregulation of the cholinergic system, the accumulation of amyloid plaques, and neurofibrillary tangles. Unfortunately, current treatments are unable to [...] Read more.
Alzheimer’s disease (AD) is a devastating neurodegenerative disease characterized by progressive neuron losses in memory-related brain structures. The classical features of AD are a dysregulation of the cholinergic system, the accumulation of amyloid plaques, and neurofibrillary tangles. Unfortunately, current treatments are unable to cure or even delay the progression of the disease. Therefore, new therapeutic strategies have emerged, such as the exogenous administration of neurotrophic factors (e.g., NGF and BDNF) that are deficient or dysregulated in AD. However, their low capacity to cross the blood–brain barrier and their exorbitant cost currently limit their use. To overcome these limitations, short peptides mimicking the binding receptor sites of these growth factors have been developed. Such peptides can target selective signaling pathways involved in neuron survival, differentiation, and/or maintenance. This review focuses on growth factors and their derived peptides as potential treatment for AD. It describes (1) the physiological functions of growth factors in the brain, their neuronal signaling pathways, and alteration in AD; (2) the strategies to develop peptides derived from growth factor and their capacity to mimic the role of native proteins; and (3) new advancements and potential in using these molecules as therapeutic treatments for AD, as well as their limitations. Full article
(This article belongs to the Special Issue Peptides for Health Benefits 2021)
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